1. Field of the Invention
The present invention relates to a continuous process for preparing N-monosubstituted 4-aminopiperidines, which are primarily employed as starting materials for preparing sterically hindered amines which serve as stabilizers for synthetic polymers and are termed H.A.L.S. (hindered amine light stabilizers).
2. Description of the Background
The preparation of N-monosubstituted 4-aminopiperidines from the corresponding 4-oxopiperidines (or 4-piperidones), primary amines and hydrogen under hydrogenation conditions, that is by reductive amination, has long been known, and has been described, inter alia, in numerous patent publications. Hitherto, this process has been carried out in one stage, or, predominantly, in two stages, and, which is of importance for the present invention, always batchwise. A continuous process of production would be very desirable. Despite attempts of numerous research and development groups, however, it has not been possible to date to develop successfully a useful continuous process.
In the two-stage batchwise procedure, in the first stage, the Schiff's base is generated, which, after removal of the water of reaction, is then catalytically hydrogenated in the second stage to give the N-monosubstituted, that is secondary, amine. In the single-stage procedure, both reactions proceed simultaneously without removal of the water of reaction.
EP 0 354 184 describes the single- or two-stage reductive amination of triacetone amine derivatives with diamines in the presence of catalytic amounts of platinum, palladium or nickel. In the two-stage variant, water is removed by distillation azeotropically and the formation of the Schiff's base is thus forced. The single-stage procedure may only be carried out in the presence of acids as co-catalyst.
Although DE 3 007 996 describes the single-stage reductive amination of 4 -piperidones with alkylamines or alkylenediamines in an inert solvent using Raney nickel or Raney cobalt as catalyst, the two-stage procedure using azeotropic removal of the reaction water, expediently with conjoint use of an ammonium salt as cocatalyst, is described as advantageous.
In the two-stage process disclosed in EP 0 033 663, various solvents are used in the two stages. In the first stage heptane is used, which at the same time functions as entrainer for the water of reaction, and in the hydrogenation stage isopropanol is used.
Clearly, it would be desirable if N-monosubstituted 4-aminopiperidines could be prepared with the same success, or even better, in only one stage. There is a series of patent publications which are specifically directed to such a procedure. EP 0 01 3 665 and EP 0 061 785 describe the single-stage reductive amination of triacetone amine derivatives with di- or higher polyamines in the presence of methanol using platinum on carbon as catalyst. However, in these methods, concentrated sulfuric acid must be used conjointly as co-catalyst.
DE 26 21 870 describes the reductive amination of alkylpiperidones with methylamine or ammonia in methanol, using 15% Raney nickel as catalyst. EP 0 208 455 discloses the single-stage reductive amination of piperidones with alkylamines or alkylenediamines in an alcohol or glycol and in the presence of cobalt, nickel or platinum catalysts. To decrease the flammability, the solvent used is alcohol/water mixtures having a water content of at least 10% by volume. A similar process using palladium as catalyst is described in EP 0 202 001.
EP 0 081 688 and 0 045 048 and JP 76-009486 describe the single-stage reductive amination of piperidones with dialkylamines or trialkylamines in methanol and in the presence of platinum on carbon as catalyst. EP 0 302 020 discloses the single-stage reductive amination of piperidones with alkylamines without solvent, with up to 10% by weight of water being permitted to remain in the reaction mixture.
Most recently, the development is again directed towards the two-stage processes, because development of the actually preferred single-stage processes to complete satisfaction has not yet been successful. For example, EP 0 508940 describes the two-stage reductive amination of piperidones with diamines. In the first stage, the Schiff's base is generated in the absence of a solvent by distilling off the water of reaction. In the second stage, the anhydrous Schiff's base is hydrogenated on palladium, platinum or Raney nickel. An apparent advantage of the process, it is that because it is a two-stage procedure, a Schiff's base of high purity is generated, a result of which is that the subsequent hydrogenation proceeds more selectively and more rapidly than hitherto, even at elevated temperatures.
The processes of the prior art which, without exception, are batchwise processes, have a number of disadvantages. For one thing, the constant start-up and shut-down of the individual batches is associated with a comparatively high labor requirement and leads additionally to low space-time yields and increased energy consumption. Most of the known processes use flammable solvents, which, on the one hand, further decrease the space/time yields, and on the other hand, necessitate higher expenditure for fire precautions and additionally also further increases in material costs. In addition, the finely particulate hydrogenation catalysts are generally pyrophoric and, therefore, even in the absence of flammable solvents, can only be handled with safety precautions, both during the initial charging, and during later batches. In addition, catalysts of this type, as is stated in EP 0 508 940, are sensitive to catalyst poisons and cannot be regenerated simply. Noble metal catalysts must be reprocessed just for reasons of cost. The disposal of nickel and cobalt catalysts is problematic, because of their toxicological properties.
The conversion rate of the starting materials and the selectivity of the formation of the desired N-monosubstituted 4 -aminopiperidine leave something to be desired, in particular in the case of the single-stage procedure, which would actually be preferred for technical reasons. This is understandable, because, in the single-stage procedure, hydrogenation of the N-substituted 4 -aminopiperidones to give the corresponding 4-aminopiperidone can take place, which hydrogenation is greatly reduced in the two-stage procedure, and, in addition, other byproducts form. However, the solvent-free crude reaction mixtures seldom contain more than 90% by weight of the target product, whose content can only be increased to 92-93% by weight by conjoint use of a co-catalyst, which then in any case must be removed again. These are contents which can be achieved by the more complex two-stage process, even without a co-catalyst, by removing the water of reaction in the first stage.
Because of the relatively low contents of the desired product in the crude reaction mixtures, it is difficult to prepare a sufficiently pure N-monosubstituted 4-aminopiperidine. According to DE 41 20 550, a single-stage batch process produces a crude reaction mixture containing 93% by weight of desired product, 0.8% by weight of starting ketone, which has an APHA value (in 10% strength by weight toluene solution) of 400 and, by conventional distillation (boiling point 180-190.degree. C., about 1 mbar) of the reaction mixture, a light solid containing&gt;99% by weight of desired product, 100 ppm of starting ketone which has an APHA value of 100. However, the product is not storage-stable, but after 3 months at 60.degree. C., shows an APHA value of&gt;1,000. Products having adequate storage stability are only obtained by a batchwise crystallization from a ketone solvent. Although the analytical data of the crystals do not differ from those of the distillate, the APHA value is only.ltoreq.30 and increases after three months at 60.degree. C. to only.ltoreq.100. It is obvious that this additional purification step is complex and undesirable.
The only known continuous process for preparing 4-alkylaminopiperidines is the reductive alkylation of 4-aminopiperidines with the corresponding alkanols as described in EP 0 128 285. The process operates with high amine excess, and only about 10% by weight of the desired product is present in the material discharged from the reaction, so that in order to increase the degree of conversion, the unreacted starting material must be separated and recycled in complex additional steps. A need, therefore, continues to exist for an effective single stage, continuous process of preparing N-monosubstituted-4-aminopiperidines by reaction of 4-oxopiperidine with a primary amine.